synonymhistocytosis(histiocytosis) generally refers to Langerhans cell histiocytosis
This entry is made byGood Doctor OnlineProvide content and participate in editing.
Ye Qiao
(Deputy Chief Physician)
Beijing Institute of Respiratory Diseases, Beijing Chaoyang Hospital, Capital Medical University
Pulmonary Langerhans' cell histiocytosis (PLCH) is a relatively rare lung disease, which usually occurs in young people, is closely related to smoking, and most of them are benign and protracted.Lung histopathology is characterized by the proliferation and infiltration of Langerhans cells, forming multiple parabronchiolar interstitial nodules and cysts in both lungs.
Langerhans' cell histiocytosis (LCH) is a group of diseases characterized by the proliferation, infiltration and granuloma formation of a large number of Langerhans' cells, leading to organ dysfunction..The organs usually involved in LCH include bone (especially skull and axial bone), lung, central nervous system (especially hypothalamus region) and skin, which are classified according to the number of involved organs (Table 4-28-1).According to the number of involved organs, LCH can be divided into two categories: single organ involvement and multi system involvement (Table 1).The former is usually associated with the involvement of a single organ (such as lung, bone, skin), which is mostly seen in adults, with a good prognosis;Most of the latter involve multiple systems, such as Letter Siwe disease and Hand Sch ü ller Christian disease, which tend to occur in children and have a poor prognosis.PLCH refers to a disease in which Langerhans cells only involve the lung or the lung is one of the organs involved in multiple systems. Its development process and prognosis are different from those of LCH involved in multiple systems.[1]
Table 1 Brief classification of adult Langerhans cell histiocytosis
Single organ involvement
Multi system involvement
-Lung (more than 85% of cases with lung involvement)
-Bones
-Skin
-Pituitary gland
-Lymph nodes
-Other parts: thyroid, liver, spleen, brain
-Multiple organ disease with lung involvement (accounting for 5%~15% of cases with lung involvement)
The incidence of PLCH is closely related to tobacco exposure. The vast majority (90% - 100%) of PLCH patients have a history of smoking, especially those who smoke more than 20 packs of years.In the past, it was believed that the incidence of PLCH in men was higher than that in women. Recent studies have found that there is no significant difference in the incidence of PLCH between men and women. This difference may be related to the increase in the number of female smokers.Most PLCH patients are heavy smokers, but PLCH can also occur in patients with short smoking history.After quitting smoking, the chest image of PLCH patients can be improved, and PLCH may recur in patients receiving lung transplantation at the end stage if they continue to smoke.Although the incidence of PLCH is related to tobacco exposure, the amount of smoking is not related to the severity of PLCH disease.A case report shows that PLCH can also develop after radiotherapy and/or chemotherapy for lymphoma.The vast majority of PLCH cases are sporadic, and there are also some reports of LCH family cases. The correlation between the incidence of PLCH and genes is still unclear.At present, there is no evidence that occupational or geographical factors are related to PLCH.In addition to tobacco, it is not clear whether virus and other exogenous substances play a role in the pathogenesis of PLCH.[2]
Pathogenesis
Announce
edit
Bombesin hypothesis believes that the increased production of bombesin like peptides plays a role in the pathogenesis of PLCH.Bombesin is a neuropeptide produced by neuroendocrine cells, which is increased in the lung of smokers.Frogskin like peptides have chemotaxis on monocytes, promote mitosis of epithelial cells and fibroblasts, and stimulate cytokine secretion.Tobacco inhalation can make airway neuroendothelial cells release bombesin like peptides (BLP), which can further activate alveolar macrophages and release cytokines, such as tumor necrosis factor alpha (TNF - α), granulocyte macrophage colony stimulating factor (GM-CSF) or other mediators, which may enhance the recruitment and activation of Langerhans cells.At the same time, bombesin polypeptide can also stimulate the proliferation of fibroblasts and promote the formation of pulmonary fibrosis.Other antigens in smoke, such as tobacco glycoprotein (TGP), are immune stimulators that can induce lymphocyte proliferation and the production of lymphokines.Nicotine in tobacco can significantly reduce the phagocytosis of dendritic cells, inhibit the production of proinflammatory factors (especially IL-12) by dendritic cells, and reduce the ability of dendritic cells to induce T cells to differentiate into T-helper cell type 1.
The expression of adhesion molecules regulating the interaction between leukocytes and endothelial cells in PLCH lung tissue has changed.The expression of intercellular adhesion molecule-1 of LCs and other leukocyte adhesion molecules such as β 1 and β 2 integrin can be seen in the lung tissue of PLCH patients.The importance of these findings and their relevance to PLCH remain to be clarified.
In addition, PLCH may be related to malignant tumors.Lymphomas, including Hodgkin's lymphoma and non Hodgkin's lymphoma, have been reported to be associated with PLCH.[3]
Pathological manifestations
Announce
edit
The pathological feature of PLCH is that Langerhans cells appear in characteristic clusters, with a significant increase in number, mainly distributed around the small airways, and their morphology is similar to that seen in normal tissues. The cytoplasm is weakly eosinophilic staining, and there is an obvious groove like nuclear membrane (Figure 1).In formalin fixed paraffin embedded tissue sections, Langerhans cytoplasm S-100 (Fig. 2a) and cell surface CD1a (Fig. 2b) were positive.Under the electron microscope, Langerhans cells can see a special structure with five layers of rods, called Birbeck particles.
The general specimen of PLCH lung showed scattered nodules with varying degrees of cystic changes in both lungs.A mass in the bronchus can also be seen, and a single nodule lesion is rare.The upper and middle lobes of the lungs are significantly affected, and the bottom of the lungs are usually not.The shape of the nodule is irregular, and the edge is star shaped.In the final stage, dense fibrosis and cystic changes were seen, presenting honeycomb lung.In the course of disease progression, the pathological manifestations are: nodules, cystic nodules, thick walled cysts, thin walled cysts.
At low magnification, scattered stellate interstitial nodules centered on bronchioles in relatively normal lung tissue are the main histopathological characteristics of PLCH. The pathological phase of PLCH is uneven, and nodules, cysts, and fiber spots coexist (Figure 3).Nodules and cysts can also be distributed along the pleura and interlobular septum.Nodules with a diameter of 1mm~5mm can be seen in most cases.The nodules contain mixed cell populations, including different numbers of Langerhans cells, eosinophils, lymphocytes, plasma cells, fibroblasts and macrophages with soot particles in their cytoplasm.As the disease progresses, the nodules gradually decrease, the cysts gradually increase, and Langerhans decreases or disappears in the final stage. Interstitial fibrosis and the formation of small cysts can be seen, and the lesions widely extend to the lung parenchyma, surrounding the bronchial vascular structure, forming a disease characteristic lesion called star damage.The lung around the nodules and cysts can be seen with respiratory bronchiolitis with interstitial lung disease (RB-ILD) and desquamated interstitial pneumonia (DIP) like reaction caused by smoking, that is, the aggregation of alveolar macrophages in the alveolar cavity of smokers.Emphysema is also common.The histopathological changes corresponding to the nodules in the chest image are stellate interstitial nodules, and the cystic shadows are dilated bronchioles.
When pneumothorax occurs, reactive eosinophilic pleurisy may occur. Mesothelial cell proliferation, chronic inflammation and eosinophilic infiltration can be seen, which is non-specific.End stage PLCH patients are accompanied by pulmonary hypertension, which is mainly related to the involvement of pulmonary arterioles and pulmonary venules. The vascular wall can see thickening of the middle membrane and intima hyperplasia. Lung Langerhans cells may participate in the reconstruction of pulmonary vessels by producing cytokines and growth factors.[4-5]
clinical manifestation
Announce
edit
The clinical manifestations of PLCH vary greatly. A quarter of patients have no respiratory symptoms, so they are easy to miss diagnosis. If symptoms occur, the most common are dry cough and dyspnea after activities.About 1/3 of the patients have systemic symptoms, such as emaciation, fatigue, fever, night sweats and anorexia.When the patient has systemic symptoms, attention should be paid to check whether there are potential tumors.About 10% of the patients have spontaneous pneumothorax due to rupture of the subpleural sac, which can be the first symptom of the disease.Chest pain is not common. During the development of the disease, about 1/5 of the patients have chest pain, although chest pain may occur when the disease involves the ribs.Hemoptysis is rare, only seen in 5% of PLCH patients, most of which are not caused by PLCH, suggesting that pulmonary mycoglobules or lung cancer may be associated.5% - 15% of patients have corresponding symptoms because Langerhans cells involve other organs or systems, such as liver or spleen, which may lead to abdominal discomfort;The superficial lymph nodes are involved, and the corresponding lymph nodes are enlarged;If hypothalamus is involved, there may be thirst and diabetes insipidus.Physical examination showed no abnormalities in the lungs, and clubbing fingers were rare.The signs of pulmonary hypertension and cor pulmonale can be seen in the end stage patients.[6]
Supplementary Examination
Announce
edit
1. At the early stage of PLCH on chest radiograph, the chest radiograph shows the infiltration of micro nodules or reticular nodules with unclear lung boundaries, mainly in the middle and upper lungs, and the costophrenic angle is usually not involved (Figure 4a).Cystic changes are characteristic changes of the disease, and can coexist with nodules.At the end of PLCH, multiple adjacent cysts with a diameter of more than 2cm can be seen, which is difficult to differentiate from emphysema or lymphangioleiomyomatosis (LAM).Pneumothorax can be seen on PLCH chest radiograph, and osteolytic damage of ribs can be seen in very few cases.Pleural effusion and hilar lymph node enlargement are rare.When pulmonary hypertension is combined, chest radiograph shows that the right lower pulmonary artery trunk is widened, the pulmonary artery segment is swollen, and the right ventricle is enlarged (Figure 4b).A few early patients (<10%) had normal chest radiographs.
2. Chest HRCT Chest HRCT has characteristic manifestations and distribution characteristics, which is an important basis for clinical diagnosis of PLCH.The early lesions were mainly centrilobular nodules with a few cystic changes (Figure 5).As the disease progresses, cysts, fibrosis and honeycombed lung appear.The change of the cystic cavity is relatively late, with irregular thickness of the cystic wall, different diameters, and diffuse distribution, especially in the middle and upper lung fields (Figure 6).In the late stage, cystic shadows can appear all over the lung.The lung lesions in PLCH patients showed a regular pattern of changes from nodules to cystic nodules, thick walled cysts, and then to thin walled cysts.
3. The decrease of carbon monoxide diffusion capacity (DLCO) in lung function was found in 60%~90% of patients.Common vital capacity (VC) and total lung capacity (TLC) decreased, and the ratio of residual volume (RV) to TLC increased.20%~30% of patients had airflow restriction, and the ratio of forced expiratory volume in the first second (FEV1) to vital capacity (VC) decreased.At the end of the disease, a few patients showed restrictive ventilation dysfunction and diffusion disorder.10%~15% patients had normal resting lung function.Arterial blood gas analysis is related to the degree of lung involvement.
4. Under bronchoscopy and bronchoalveolar lavage bronchoscopy, there was no abnormal manifestation of trachea and bronchus, or tracheobronchial mucosa showed non-specific inflammatory changes related to smoking.Bronchial mucosal biopsy is not helpful for diagnosis, but it is helpful for excluding other diagnoses.Because the lung lesions are focally distributed, the diagnostic rate of transbronchial lung biopsy (TBLB) is low (10%~40%), and PLCH lungs are cystic lesions, which increases the risk of pneumothorax.Cell analysis of bronchoalveolar lavage fluid (BALF) is helpful for diagnosis and differential diagnosis. The number of CD1a (OKT6) positive Langerhans cells in BALF is more than 5% (normal less than 1%). Combined with chest imaging, it can indicate the diagnosis of PLCH, but the sensitivity is low (25%~50%), because in many diseases, CD1a positive cells in BALF are increased to varying degrees (2% - 5%).It is worth noting that for smokers with normal chest image, CD1a positive cells in BALF can reach 3%.BALF analysis is helpful to differentiate diffuse lung diseases such as sarcoidosis, allergic pneumonia, tuberculosis, lung cancer and alveolar hemorrhage.
5. Surgical lung biopsy The lung tissue obtained from surgical lung biopsy is accurate and has high diagnostic value.Although surgical lung biopsy is the gold standard for disease diagnosis, it has a certain degree of trauma. If we master the clinical manifestations and typical imaging data, we can make clinical diagnosis and avoid surgical lung biopsy.
6. Laboratory tests are not specific, and peripheral blood eosinophils, immunoglobulins, autoantibodies, and serum angiotensin converting enzyme are usually in the normal range.
disease diagnosis
Announce
edit
In young and middle-aged smokers, HRCT of the chest showed diffuse nodules and cystic shadows in both lungs, with the upper middle lung field as the focus, not involving the costophrenic angle. Combined with more than 5% of CD1a positive Langerhans cells in BALF, PLCH can be clinically diagnosed.Because the tissue mass obtained by TBLB is small and the positive rate of diagnosis is low, surgical lung biopsy is usually required for cases that cannot be diagnosed clearly in clinical practice.Pathology of lung tissue showed typical stellate interstitial nodules and cysts centered on bronchioles. Lung Langerhans cells were positive for CD1a and S-100 staining, which can be diagnosed.For patients diagnosed with PLCH, the involvement of extrapulmonary organs, such as hip bone (Figure 7), skin, pituitary, lymph nodes, thyroid, liver and spleen, should also be examined.PLCH cannot usually be diagnosed if the patient has no history of tobacco exposure.
Disease treatment
Announce
edit
1. Quitting smoking and quitting smoking is the first therapeutic measure. 50%~75% of patients are stable or improved 6~24 months after quitting smoking, with symptoms relieved and imaging lesions partially or completely disappeared (Fig. 8a, b). At the same time, quitting smoking can also reduce the risk of lung cancer, chronic obstructive pulmonary disease, and cardiovascular and cerebrovascular diseases.
2. Glucocorticoid can be used empirically in patients with systemic symptoms and worsening imaging or pulmonary function.The initial dose of prednisone was 0.5 mg/kg~1 mg/kg per day, and then gradually decreased for 6~12 months.However, the efficacy of hormone has not been confirmed.
3. Cytotoxic drugs Cytotoxic drugs such as vincristine, methotrexate, cyclophosphamide, etoposide and cladribine can be used for patients with multiple organ involvement who have no remission after smoking cessation or have no response to hormone therapy.The efficacy of cytotoxic drugs is unclear.
4. Lung transplantation should be considered for PLCH patients with severe respiratory failure or pulmonary hypertension at the end of lung transplantation.Before lung transplantation, patients must quit smoking;After lung transplantation, if the patient smokes again, the transplanted lung may still develop PLCH again.[7]
Disease prognosis
Announce
edit
The natural course and prognosis of the disease vary greatly among individuals. About 50% of the patients have a good prognosis, with symptoms and imaging showing partial or complete remission. 30% to 40% of PLCH patients have progressive and continuous disease progress, and 10% to 20% of patients have progressive and severe symptoms, such as repeated pneumothorax, respiratory failure and pulmonary hypertension.The factors of poor prognosis of PLCH include high age of onset, persistent systemic symptoms, repeated pneumothorax, extrapulmonary involvement, diffuse cystic changes in the lung, and pulmonary hypertension.The 1-year, 2-year and 5-year survival rates were 63.6%, 57.2% and 53.7% respectively. 20% (8/29 cases) of PLCH recurred after lung transplantation. Smoking and extrapulmonary involvement may be risk factors for recurrence.
disease prevention
Announce
edit
PLCH is a smoking related interstitial lung disease. Non smoking or quitting smoking can prevent the occurrence of PLCH.
